1. Field of the Invention
The present invention provides a screening method for identifying compounds which induce tardive dyskinesia (TD) when administered to an animal.
2. Related Art
Tardive dyskinesia (TD) is a debilitating side effect of long-term antipsychotic exposure. This movement disorder affects 20-40% or more of patients treated chronically with antipsychotic drugs (Morgenstern, H. and Glazer, W. M., et al., Arch. Gen. Psychiat. 50:723-733 (1993)) and roughly 4-5% of patients are expected to develop TD with each year of antipsychotic treatment. The manifestations of TD may include adventitious movements of the oral-facial region, choreoathetosis of extremities and lordotic posturing. Despite the recent arrival of atypical antipsychotics such as clozapine and olanzapine, large numbers of patients continue to receive conventional antipsychotics.
The pathophysiologic basis for antipsychotic-induced TD remains unclear. While the theory that striatal postsynaptic dopamine receptor supersensitivity causes TD has been widely accepted for two decades, some evidence contradicts this model (Jenner, P. and Marsden, C. D., TINS 9:259-260 (1986)). Although acute administration of antipsychotics temporarily increases the firing of dopamine neurons, chronic antipsychotic treatment leads to a decrease in their firing rate due to depolarization blockage (Cadet, J. L. and Lohr, J. B., Ann. N.Y. Aca. Sci. 570:176-185 (1989)). After an acute elevation of dopamine turnover with haloperidol treatment, dopamine synthesis and release decreases; and dopamine metabolite levels return to normal with chronic treatment (Rastogi, S. K., et al., Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 7:153-164 (1983)). Notably, striatal dopamine metabolites are reduced in monkeys with dyskinesia due to long-term antipsychotic treatment. Finally, post mortem neurochemical studies have not revealed a correlation between dopamine receptor up-regulation and TD (Crow, T. J., et al., Journal of Clinical Psychopharmacology 2:336-340 (1982). Thus, excessive activation of postsynaptic striatal dopamine receptors is not consistent with the time course nor persistence of TD.
An alternative hypothesis supports a neurodegenerative process affecting striatal efferent neurons analogous to Huntington's disease and Wilson's disease. TD is similar to these diseases in that all three diseases present choreoathetoid movements and pathological changes in the striatum. Christensen et al. (Christensen, E., et al., Acta Psychiatrica Scandinavica 46:14-23 (1970)) reported neuronal loss in the basal ganglia of patients with persistent TD; similar losses have been described in rats treated chronically with antipsychotics (Pakkenberg, H., et al., Psychopharmacologia 29:329-336 (1973); Nielsen, E. B. and Lyon, M., Psychopharmacology 59:85-89 (1978); Gunne, L. M. and Andren, P. E., Clin. Neuropharmacol. 16:90-95 (1993)). Importantly, loss of the presynaptic markers for the striatal-pallidal and nigral GABAergic neurons, glutamic acid decarboxylase (GAD) and .gamma.-aminobutyric acid (GABA), have been observed in a primate model for TD and in post mortem studies of patients with TD (Gunne, L. M., et al., Nature 309:347-349 (1984); Gunne, L. M. and Haggstrom, J. E., Journal of Clinical Psychiatry 46:48-50 (1985); Anderson, U., et al., Movement Dis. 4:37-46 (1989)).
Both preclinical and clinical studies point to degeneration of striatal efferent neurons, especially GABAergic neurons, in TD. Although inconclusive, one brain imaging study has revealed reduction in the volume of the caudate nuclei in patients with TD in comparison to patients without TD and normal controls (Mion, C. C., el al., Psychiatry Research 40:157-166 (1991)). In the primate model of experimental TD, antipsychotic induced dyskinetic monkeys exhibit a reduction in presynaptic GABAergic markers in the subthalamic nucleus, the medial segment of globus pallidus and rostral part of the substantia nigra (Gunne, L. M., et al., Nature 309:347-349 (1984)). Rodent models of TD have also revealed a significantly lower density of large neurons in the striatum (Jeste, D. V., et al., Psychopharmacology 106:154-160 (1992)), and decreased GAD activity in the substantia nigra (Gunne, L. M. and Haggstrom, J. E., Journal of Clinical Psychiatry 46:48-50 (1985); Jester D. V., el al., Psychopharmacology 106:154-160 (1992)). Finally, Mitchell et al. have recently demonstrated rat apoptotic neuronal death in the striatum as a consequence of removal of the nigrostriatal dopaminergic pathway, similar to antipsychotic drug induced dopamine antagonism (Mitchell, I. J., et al., Neuroscience 63:1-5 (1994)).
We have found elevated levels of CSF N-acetylaspartate (NAA) in TD patients. This finding is consistent with a neuronal degenerative process since CSF NAA, a marker for neuronal integrity, is elevated in amyotrophic lateral sclerosis (Rothstein, J. D., et al., Ann. Neurol. 28:18-25 (1990)); and tissue NAA levels decrease in areas involved in active neuronal degeneration in amyotrophic lateral sclerosis, Huntington's Disease and Alzheimer's Disease (for a review, Tsai, G. and Coyle, J. T., Prog. in Neurobiol. 56:531-540 (1995)).
The incidence rate of TD increases throughout the patient's exposure to antipsychotic drugs. The longer the exposure, the higher the patient's risk of developing TD. This phenomenon points to the inadequacy of preclinical trials which only assess the risk of TD during the trial period. This phenomenon also suggests that the neuronal insults associated with TD are cumulative and the process which leads to this disease may be insidious and subtle in nature.
There is accumulating evidence suggesting that antipsychotics can induce oxidative stress through a variety of mechanisms. Elevated levels of conjugated dienes and thiobarbituric acid reactive products (TBARS) in the CSF of TD patients have been reported (Pall, H. S., et al., Lancet ii:596-599 (1987); Lohr, J. B., et al., Biol. Psychial. 28:535-539 (1990); Jeste, D. V., et al., Psychopharmacology 106:154-160 (1992)).
Elevated oxyradicals can inhibit presynaptic glutamate uptake, inactivate the enzymatic defenses against cellular oxidants (Volterra, A., et al, J. Neuroscience 14:2924-2932 (1994)) and disrupt mitochondrial electron transport (Burkhardt, C., et al., Ann. Neurol. 33:512-517 (1993); Jackson-Lewis, V. and Przedborski, S., Ann. Neurol. 35:244-245 (1994)), which results in an increased generation of superoxide and extraneuronal excitatory amino acids. Persistent activation of glutamate ionotropic receptors has long been known to cause neuronal degeneration (Olney, J. W., Annu. Rev. Pharmacol. Toxicol. 30:47-41 (1990)). Recent studies indicate that oxidative damage mediates the delayed neuronal degeneration caused by activation of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate ionotropic receptors (Coyle, J. T. and Puttfarcken, P., Science 262:689-695 (1993)). This oxidative damage can be gradual, insidious and cumulative leading to an apoptotic form of neuronal death. It provides an important pathologic link between moderate levels of excessive glutamate ionotropic receptor stimulation and delayed neuronal degeneration.
The sources of oxyradicals produced as a consequence of long-term antipsychotic exposure are diverse and remain incompletely characterized. Depolarization activates oxidative metabolism of glucose via the mitochondrial electron transport chain with the superoxide radical generated as a byproduct. Recent reports indicate that antipsychotics inhibit the mitochondrial electron transport chain at Complex I, which would further enhance superoxide generation (Burkhardt, C., et al., Ann. Neurol. 33:512-517 (1993); Jackson-Lewis, V. and Przedborski, S., Ann. Neurol. 35:244-245 (1994)), and CSF metabolic abnormalities found in this cohort of patients is consistent with an impairment of mitochondrial electron transport at Complex I (Goff, D. C., et al., Amer. J. Psychiat. 152:1730-1736 (1995)). Another possibility, however, is that an increased turnover of catecholamines results in free-radical formation. Nevertheless, it is unclear whether antipsychotics can directly generate free radicals and a reliable screening method for the potential of antipsychotic-induced TD does not exist.
The hypothesis of oxidative damage to striatal neurons mediated by antipsychotic enhancement of glutamatergic neurotransmission is supported by recent reports that Vitamin E reverses the symptoms of TD. The anecdotal reports have been sustained by double blind placebo controlled studies with Vitamin E (Egan, M. F., et al., Amer. J. Psychiat. 149:773-777 (1992); Adler, L. A., et al., Amer. J. Psychiat. 150:1405-1407 (1993)). Notably, those patients earlier in the course of their disorder are more responsive to treatment with Vitamin E, consistent with the model that the oxidative damage is cumulative over time and involves functional impairment prior to frank degeneration. Similarly, in a double blind placebo controlled study of Vitamin E treatment of patients with Huntington's Disease, those who were less symptomatic at the initiation of treatment exhibited the most favorable response (Peyser, C. E., et al., Amer. J. Psychiatry 152:1771-1775 (1995)). Inasmuch as centrally active free radical scavengers may not only reverse the oxidative damage, additional studies on oxidative stress in TD as well as efficacy of prevention and treatment with centrally active free radical scavengers on the surrogates oxidative stress in TD need to be carried out.
One of the major sources of potential oxidative stress in the brain is redox active metals (reviewed in Markesbery, W. R., Free Radic. Biol. Med. 23: 134-147 (1997)). Iron and copper are highly concentrated in the basal ganglia. Reduction of iron (III) and copper (II) generates iron (II) and copper (I), respectively. In Wilson's disease, there is progressive accumulation of copper within the body tissues, particularly the erythrocytes, kidney, liver and brain. In the blood, more than 90% is found in the plasma associated with ceruloplasmin. Copper absorption appears to be accelerated, and although the urinary excretion of free copper is usually increased, affected individuals of Wilson's disease are in positive copper balance. In addition to Wilson's disease, abnormal copper metabolism exists in the neurodegenerative disorders of Menkes' syndrome and possibly familial amyotrophic lateral sclerosis. Caudate, putamen, cerebral cortex and the dentate nuclei are the vulnerable regions in Wilson's disease. When cerebral copper accumulation is sufficient to destroy the nerve cells, the neurological syndrome begins. The most common features of this disease include choreoathetoid movements, muscular rigidity, and tremor of the extremities which have remarkable similarity to the symptoms of TD.
Although the relevance of oxidative stress to TD is becoming clear, a rational neurochemical basis for developing antipsychotics devoid of TD is lacking. While Vitamin E treatment has been used with some success, drugs aiming at the source of oxidative stress in TD is missing. The application of other antioxidants will not address the underlying pathogenesis mechanism.